Innate immune response restarts adaptive immune response in tumors.

The imbalance of immune response plays a crucial role in the development of diseases, including glioblastoma. It is essential to comprehend how the innate immune system detects tumors and pathogens. Endosomal and cytoplasmic sensors can identify diverse cancer cell antigens, triggering the production of type I interferon and pro-inflammatory cytokines. This, in turn, stimulates interferon stimulating genes, enhancing the presentation of cancer antigens, and promoting T cell recognition and destruction of cancer cells. While RNA and DNA sensing of tumors and pathogens typically involve different receptors and adapters, their interaction can activate adaptive immune response mechanisms. This review highlights the similarity in RNA and DNA sensing mechanisms in the innate immunity of both tumors and pathogens. The aim is to enhance the anti-tumor innate immune response, identify regions of the tumor that are not responsive to treatment, and explore new targets to improve the response to conventional tumor therapy and immunotherapy.

Effect of renal denervation for patients with isolated systolic hypertension: a systematic review and meta-analysis.

BACKGROUND: Renal denervation (RDN) is a promising treatment based on catheter intervention for patients with refractory hypertension. However, the effect in patients with isolated systolic hypertension (ISH) remains controversial. The aim of this meta-analysis was to determine the blood pressure lowing effect of RDN in patients with ISH compared with combined systolic/diastolic hypertension (CH) patients. METHODS: PubMed, Embase, Cochrane and ClinicalTrials.gov were searched for prospective clinical studies that included RDN. The outcomes of interest were the change of 24-hour ambulatory systolic blood pressure (SBP) from baseline. We used the fixed effects model to calculate weighted mean difference (WMD) with 95% confidence interval (CI). RESULTS: Six trials were included, with 1405 participants, including 597 patients with ISH and 808 patients with CH. Mean follow-up was five months. The reduction of 24-hour ambulatory SBP was significantly greater for the CH patients than the ISH patients (WMD = 3.89, 95% CI: 2.32-5.45, P < 0.0001). RDN also showed a greater reduction in office SBP in the CH patients compared to the ISH patients (WMD = 10.24, 95% CI: 4.24-15.74, P = 0.0003). And the effect was independent of age, length of follow-up, and ablation device. CONCLUSIONS: RDN provides superior blood pressure control in the CH patients compared with the ISH patients, and the CH patients may be the best suitable population for which RDN is indicated.

Ablation strategies for arrhythmogenic right ventricular cardiomyopathy: a systematic review and meta-analysis.

BACKGROUND: Catheter ablation for ventricular tachycardia (VT) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has significantly evolved over the past decade. However, different ablation strategies showed inconsistency in acute and long-term outcomes. METHODS: We searched the databases of Medline, Embase and Cochrane Library through October 17, 2019 for studies describing the clinical outcomes of VT ablation in ARVC. Data including VT recurrence, all-cause mortality, acute procedural efficacy and major procedural complications were extracted. A meta-analysis with trial sequential analysis was further performed in comparative studies of endo-epicardial versus endocardial-only ablation. RESULTS: A total of 24 studies with 717 participants were enrolled. The literatures of epicardial ablation were mainly published after 2010 with total ICD implantation of 73.7%, acute efficacy of 89.8%, major complication of 5.2%, follow-up of 28.9 months, VT freedom of 75.3%, all-cause mortality of 1.1% and heart transplantation of 0.6%. Meta-analysis of 10 comparative studies revealed that compared with endocardial-only approach, epicardial ablation significantly decreased VT recurrence (OR: 0.50; 95% CI: 0.30-0.85; P = 0.010), but somehow increased major procedural complications (OR: 4.64; 95% CI: 1.28-16.92; P= 0.02), with not evident improvement of acute efficacy (OR: 2.74; 95% CI: 0.98-7.65; P = 0.051) or all-cause mortality (OR: 0.87; 95% CI: 0.09-8.31; P = 0.90). CONCLUSION: Catheter ablation for VT in ARVC is feasible and effective. Epicardial ablation is associated with better long-term VT freedom, but with more major complications and unremarkable survival or acute efficacy benefit.

Relationship between red blood cell distribution width levels and atrial fibrillation in hypertensive patients.

BACKGROUND: Information on the relationship between red blood cell distribution width (RDW) and atrial fibrillation (AF) in patients with essential hypertension are scarce. The study aimed to assess the relationship between AF and RDW in hypertensive patients. METHODS: We enrolled 432 hypertensive patients, including 350 AF patients and 82 patients as controls. Patients' demographic, clinical, laboratory and echocardiographic characteristics were recorded. The AF patients were further divided into the persistent and paroxysmal AF subgroups. Electrocardiograms were monitored to identify the cardiac rhythm during blood sampling, and based on the rhythm, the paroxysmal AF group was categorized into the presence (with AF rhythm during blood sampling) and absence (with sinus rhythm during blood sampling) groups. RESULTS: The AF group had elevated RDW levels than the controls (12.7% ± 0.8% vs. 12.4% ± 0.7%, P = 0.002), and the persistent AF subgroup had higher RDW levels than the paroxysmal AF subgroup (12.9% ± 0.8% vs. 12.6% ± 0.8%, P = 0.007). Furthermore, in the paroxysmal AF group, the presence group had higher RDW levels than the absence group (13.0% ± 0.6% vs. 12.5% ± 0.9%, P = 0.001). There was no significant difference in RDW levels between the persistent AF subgroup and presence group of the paroxysmal AF subgroup (P = 0.533) and between the absence group of the paroxysmal AF subgroup and control group (P = 0.262). In multivariate regression analysis, in hypertensive patients, the presence of AF rhythm is an independent predictor for increased RDW concentration (P = 0.001). CONCLUSIONS: The RDW may be associated with the presence of AF rhythm, which implies the importance of maintaining the sinus rhythm in hypertensive patients.

Correlations between low thyroid function and incidence of atrial fibrillation in hypertrophic obstructive cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic obstructive cardiomyopathy (HOCM). Data regarding the correlations of thyroid dysfunction and the incidence of AF in HOCM are quite limited. This study aimed to reveal the correlations between different thyroid status and the corresponding incidence of AF in a large HOCM cohort. METHODS: A total of 806 HOCM patients with complete information on thyroid function tests and comprehensive cardiac evaluations were recruited. The participants were divided into the AF group (n = 159) and non-AF group (n = 647) according to established medical history and results of Holter monitoring. The thyroid status of the study population and the corresponding incidence of AF were assessed and analyzed. RESULTS: Hypothyroidism accounted for the greatest proportion of thyroid dysfunction in HOCM patients. The incidence of AF significantly increased in individuals with both overt (P = 0.022) and subclinical (P = 0.007) hypothyroidism. Compared with participants in the non-AF group, those with positive AF episodes presented with lower free triiodothyronine (FT3) (2.86 ± 0.52 pg/mL vs. 3.01 ± 0.42 pg/mL, P = 0.001), higher free thyroxine (FT4) (1.24 ± 0.25 ng/dL vs. 1.15 ± 0.16 ng/dL, P < 0.001), and remarkably increased levels of thyrotropin (TSH) (12.6% vs. 5.3%, P = 0.001). Multivariable analyses demonstrated that the concentrations of FT3 (odds ratio [OR] = 0.470, 95% confidence interval [CI]: 0.272-0.813, P = 0.007) and FT4 (OR = 17.992, 95% CI: 5.750-56.296, P < 0.001), as well as TSH levels above normal ranges (OR = 2.276, 95% CI: 1.113-4.652, P = 0.024) were independently associated with the occurrence of AF in the large HOCM cohort. CONCLUSIONS: This study indicated a strong link between low thyroid function and the presence of AF in HOCM. Hypothyroidism (both overt and subclinical states) seems to be valuable for assessing the incidence of AF in patients with HOCM.

Association between big endothelin-1 and CHADS2/CHA2DS2-VASc scores in non-valvular atrial fibrillation.

BACKGROUND: Endothelial function, as measured by big endothelin-1 (ET-1), has been demonstrated to be useful in predicting adverse long-term events in patients with cardiovascular disease. Nevertheless, there are little data about the association between big ET-1 and thromboembolism risk in atrial fibrillation (AF). We aimed to investigate the relationship between big ET-1 and CHADS2/CHA2DS2-VASc scores used for evaluating thromboembolic risk in patients with non-valvular AF. METHODS: The study population consisted of 238 consecutive AF patients (67.6% with paroxysmal AF and 32.4% with persistent AF). The patients were divided into two groups (high- or low-intermediate risk group) based on CHADS2 and CHA2DS2-VASc scores (score ≥ 2 or < 2, respectively). Clinical, laboratory, and echocardiographic parameters were evaluated, and the CHADS2/CHA2DS2-VASc scores were compared between groups. The association between big ET-1 levels and CHADS2/CHA2DS2-VASc score was assessed. Multivariate logistic regression analysis was performed to identify independent predictors of CHADS2/CHA2DS2-VASc scores. RESULTS: The high CHADS2/CHA2DS2-VASc score group had older age, higher big ET-1 levels, and enlarged left atrial diameter than the low CHADS2/CHA2DS2-VASc score group (P < 0.05). Multiple logistic regression analysis revealed that big ET-1 level was an independent determinant of high CHADS2/CHA2DS2-VASc scores [odds ratio (OR) = 2.545 and OR = 3.816; both P < 0.05]. CONCLUSIONS: Our study indicates that in non-valvular AF, big ET-1 was significantly correlated with CHADS2/CHA2DS2-VASc scores and an independent predictor of high CHADS2/CHA2DS2-VASc scores. Big ET-1 may serve as a useful marker for risk stratification in this setting.

Hydrogen sulfide improves endothelial dysfunction in hypertension by activating peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase signaling.

OBJECTIVE: We aimed to elucidate the ameliorative effect of hydrogen sulfide (H2S) on endothelium-dependent relaxation disturbances via peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase (PPARδ/eNOS) pathway activation in hypertensive patients and rats. METHODS: Renal arteries were collected from normotensive and hypertensive patients who underwent nephron-sparing surgery. Renal arteries from 37 patients were cultured with or without sodium H2S (NaHS) 50 µmol/l. The rats were randomly divided into four groups: Sham; Sham + NaHS, two kidneys; one clipped (2K1C); and 2K1C + NaHS. Mean arterial pressure was measured by tail-cuff plethysmography. A microvessel recording technique was used to observe the effect of NaHS on endothelium-dependent relaxation. Plasma H2S concentrations were detected using the monobromobimane method. Real-time PCR and western blotting were used to assess mRNA and protein levels of AT1, cystathionine γ-lyase, PPARδ, and phosphor-eNOS. Laser confocal scanning microscopy measured intracellular NO production in human umbilical vein endothelial cells. RESULTS: NaHS improved endothelial function in hypertensive humans and rats. The 20-week administration of NaHS to 2K1C rats lowered the mean arterial pressure. In human umbilical vein endothelial cells, NaHS improved the AngII-induced production of NO. NaHS upregulated PPARδ expression, increased protein kinase B (Akt) or adenosine monophosphate kinase-activated protein kinase (AMPK) phosphorylation, and enhanced eNOS phosphorylation. A PPARδ agonist could mimic the ameliorative effect of NaHS that was suppressed by PPARδ, AMPK, or Akt inhibition. CONCLUSION: H2S plays a protective function in renal arterial endothelium in hypertension by activating the PPARδ/PI3K/Akt/eNOS or PPARδ/AMPK/eNOS pathway. H2S may serve as an effective strategy against hypertension.

Hydrogen Sulfide Improves Myocardial Remodeling via Downregulated Angiotensin â ¡/AT1R Pathway in Renovascular Hypertensive Rats.

BACKGROUND: Hydrogen sulfide (H2S) is an important endogenous gaseous transmitter in many physiological functions. Plasma H2S decreased, and angiotensin II (Ang II) type 1 receptor (AT1R) increased in the myocardial tissues in 2-kidney 1-clip (2K1C) rats than in normotensive rats. Accumulating evidences suggest that H2S inhibited Ang II/AT1R pathway to regulate cardiovascular function. Therefore, we hypothesized that H2S may exert beneficial effects on myocardial remodeling in 2K1C rat models of renovascular hypertension. METHODS AND RESULTS: Sodium hydrosulfide (NaHS, 56 µmol/kg/day) was administered intraperitoneally to the rats from the 7th day after 2K1C operation. Systolic blood pressure was significantly increased from the first week after the operation and was lowered after NaHS treatment for 4 weeks. H2S could also inhibit the ratio of left ventricle and septum weight to body weight, improve cross-sectional area, and ameliorate ventricular dysfunction. Additionally, the protein expression of AT1R and Ang II serum content were downregulated, whereas superoxide dismutase (SOD) protein was upregulated in 2K1C rats by NaHS treatment for 4 weeks. Furthermore, the reactive oxygen species level and AT1R protein were increased, whereas SOD protein was decreased in cardiomyocytes treated with Ang II compared with the control group. NaHS could reverse these changes. Losartan and N-acetylcysteine could also reverse Ang II-induced changes. CONCLUSIONS: The protective effect of H2S is attributable to the suppression of oxidative stress. This process involves the inhibition of the Ang II/AT1R pathway and upregulation of antioxidant enzymes in 2K1C rats.

The enhancing effect of genistein on apoptosis induced by trichostatin A in lung cancer cells with wild type p53 genes is associated with upregulation of histone acetyltransferase.

Genistein has been shown to enhance the antitumor activity of trichostatin A (TSA) in human lung carcinoma A549 cells. However, whether the combined treatment exerts the same effect in other lung cancer cells is unclear. In the present study we first compared the enhancing effect of genistein on the antitumor effect of TSA in ABC-1, NCI-H460 (H460) and A549 cells. Second, we investigated whether the effects of genistein are associated with increased histone/non-histone protein acetylation. We found that the enhancing effect of genistein on cell-growth-arrest in ABC-1 cells (p53 mutant) was less than in A549 and H460 cells. Genistein enhanced TSA induced apoptosis in A549 and H460 cells rather than in ABC-1 cells. After silencing p53 expression in A549 and H460 cells, the enhancing effect of genistein was diminished. In addition, genistein increased TSA-induced histone H3/H4 acetylation in A549 and H460 cells. Genistein also increased p53 acetylation in H460 cells. The inhibitor of acetyltransferase, anacardic acid, diminished the enhancing effect of genistein on all TSA-induced histone/p53 acetylation and apoptosis. Genistein in combination with TSA increased the expression of p300 protein, an acetyltransferase, in A549 and NCI-H460 cells. Furthermore, we demonstrated that genistein also enhanced the antitumor effect of genistein in A549-tumor-bearing mice. Taken together, these results suggest that the enhancing effects of genistein on TSA-induced apoptosis in lung cancer cells were p53-dependent and were associated with histone/non-histone protein acetylation.

Gene transfer of cystathionine ß-synthase into RVLM increases hydrogen sulfide-mediated suppression of sympathetic outflow via KATP channel in normotensive rats.

Hydrogen sulfide has been shown to have a sympathoinhibitory effect in the rostral ventrolateral medulla (RVLM). The present study examined the function of cystathionine ß-synthase (CBS)/hydrogen sulfide system in the RVLM, which plays a crucial role in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding CBS (AdCBS) or enhanced green fluorescent protein (AdEGFP) were transfected into the RVLM in normotensive rats. Identical microinjection of AdCBS into the RVLM had no effect on systolic blood pressure and heart rate (HR) in conscious rats. Acute experiments were performed at day 7 after gene transfer in anesthetized rats. Microinjection of the CBS inhibitors hydroxylamine (HA) or amino-oxyacetate into the RVLM produced an increase in the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and HR. There was a potentiation of the increases in RSNA, MAP, and HR because of the CBS inhibitors in AdCBS-injected rats compared with AdEGFP-injected rats. Pretreatment with pinacidil, a ATP-sensitive potassium (KATP) channel activator, abolished the effects of HA in two groups. Microinjection of glibenclamide, a KATP channel blocker, produced increases in RSNA, MAP, and HR in AdCBS-injected rats. No changes in behavior were observed in AdEGFP-injected rats. Furthermore, Western blot analysis indicated an increase in the expression of sulfonylurea receptor 2 and inward rectifier K(+) 6.1 in AdCBS-injected rats. These results suggest that the increase in KATP channels in the RVLM may be responsible for the greater sympathetic outflow and pressor effect of HA in AdCBS-injected rats compared with AdEGFP-injected rats.

Cystathionine-ß-Synthase Gene Transfer Into Rostral Ventrolateral Medulla Exacerbates Hypertension via Nitric Oxide in Spontaneously Hypertensive Rats.

BACKGROUND: Rostral ventrolateral medulla (RVLM) plays a crucial role in the central regulation of cardiovascular functions. Cystathionine-ß-synthase (CBS) is a major hydrogen sulfide (H2S)-generating enzyme that has been identified mainly in the brain. The present study was designed to examine CBS expression and determine its roles and mechanisms of regulating sympathetic outflow and blood pressure (BP) in the RVLM in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: CBS expression was decreased in the RVLM in SHR compared to Wistar-Kyoto (WKY) rats. Accumulating evidences suggest that H2S interacts with nitric oxide (NO) to regulate cardiovascular function. Therefore, we hypothesize that the decrease in CBS expression in the RVLM may be involved in the disorder of l-arginine/NO pathway, which subsequently affects BP in SHR. Overexpression of CBS in the RVLM caused significant increases in BP, heart rate, and urinary norepinephrine excretion in SHR but not in WKY. Acute experiments were carried out at day 7 after gene transfer. NO metabolite levels, neuronal NO synthase, and γ-amino butyric acid were decreased in SHR after CBS gene transfer. Furthermore, pressor responses to microinjection of NG-monomethyl-l-arginine into RVLM were blunt in SHR transfected with AdCBS compared to SHR transfected with AdEGFP. CONCLUSIONS: Overexpression of CBS in the RVLM elicits enhanced pressor responses in SHR, but not in WKY, and the NO system is involved in these effects. The results suggest that alterations of H2S signaling in the brain may be associated with the development of hypertension.